Stroke is presently recognized as the third leading cause of adult disability and death in the United States and Europe. In the past decade, several therapeutic approaches for the minimization of stroke-related brain damage have been pursued including inhibitors of AMPA/kainate, N-methyl-D-aspartate (NMDA) and adenosine reuptake inhibitors. It is the object of the present invention to provide novel compounds that will modulate potassium channels, in particular, large-conductance calcium-activated potassium (BK) channels which will be useful in reducing neuronal damage during ischemic conditions of a stroke episode.
Potassium channels play a key role in regulation of cell membrane potential and modulation of cell excitability. Potassium channels are themselves regulated by voltage, cell metabolism, calcium ion and receptor mediated processes. [Cook, N.S., Trends in Pharmacol. Sciences, 9, pp. 21-28 (1988); and Quast, U. and Cook, N.S., Trends in Pharmacol. Sciences, 10, pp. 431-435 (1989)]. Calcium-activated potassium (K.sub.Ca) channels are a diverse group of ion channels that share a dependence on intracellular calcium ions for activity. The activity of K.sub.Ca channels is regulated by intracellular [Ca.sup.2+ ], membrane potential and phosphorylation. On the basis of their single-channel conductances in symmetrical K.sub.+ solutions, K.sub.Ca channels are divided into three subclasses: large conductance (BK)&gt;150 pS; intermediate conductance 50-150 pS; small conductance &lt;50 pS. ("pS" stands for picosiemen, a unit of electrical conductance.) Large-conductance calcium-activated potassium (BK) channels are present in many excitable cells including neurons, cardiac cells and various types of smooth muscle cells. [Singer, J. J. and Walsh, J. V., Pflugers Archiv., 408, pp. 98-111 (1987); Baro, I., and Escande, D., Pflugers Archiv., 414 (Suppl. 1), pp. S168-S170 (1989); and Ahmed, F. et al., Br. J. Pharmacol., 83, pp. 227-233 (1984)].
Potassium ions play a dominant role in controlling the resting membrane potential in most excitable cells and in maintaining the transmembrane voltage near the K.sup.+ equilibrium potential (E.sub.k) of about -90 mV. It has been shown that opening of potassium channels shifts the cell membrane potential towards the equilibrium potassium membrane potential (E.sub.k), resulting in hyperpolarization of the cell. [Cook, N. S., Trends in Pharmacol. Sciences, 9, pp. 21-28 (1988]. Hyperpolarized cells show a reduced response to potentially damaging depolarizing stimuli. BK channels which are regulated by both voltage and intracellular Ca.sup.2+ act to limit depolarization and calcium entry and may be particularly effective in blocking damaging stimuli. Therefore cell hyperpolarization via opening of BK channels may result in protection of neuronal cells under ischemic conditions.
The role of potassium channels in the operation of the smooth muscle of the human urinary bladder is discussed by S. Trivedi, et al. in Biochemical and Biophysical Research Communications, (1995), 213, No.2, pp. 404-409.
A range of synthetic and naturally occurring compounds with BK opening activity have been reported. The avena pyrone extracted from avena sativa-common oats has been identified as a BK channel opener using a lipid bi-layer technique [International Patent application WO 93/08800, published May 13,1993]. The flavanoid, Phloretin has been found to affect the opening of Ca.sup.2+ -activated potassium channels in myelinated nerve fibers of Xenopus laevis using outside-out patches [Koh, D-S., et al., Neuroscience Lett., 165, pp.167-170 (1994)]. U.S. Pat. No. 3,971,803 issued to S. Rosenberger and K. Schwarzenbach on Jul. 27, 1976, relates to compounds of Formula (i): ##STR2##
wherein
R.sub.1 is alkyl, cycloalkyl or aralkyl; PA1 R.sub.2 is hydrogen or R.sub.1 ; PA1 R.sub.3 is hydrogen or C.sub.1-4 alkyl; PA1 Y and Z are independently O or S; PA1 R.sub.4 is either (1), if m=1, C.sub.1-8 alkylene, --C.sub.x H.sub.2x -Q-C.sub.y H.sub.2y --(Q is O or S, x and y are integers whose sum is 2 to 4), phenylene, diphenylene or naphthalene or a ##STR3## PA1 R.sup.1 is a hydrogen, C.sub.1-4 alkyl, --CR.sup.3 R.sup.4 CO.sub.2 H, --(CH.sub.2).sub.2 -NR.sup.5 R.sup.6; and ##STR9## PA1 R.sup.2 is hydrogen, C.sub.1-4 alkyl; or R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached, is a heterocyclic ring selected from piperazine, N-methyl piperazine, piperidine, thiomorpholine, morpholine and ##STR10## PA1 R.sup.3 is hydrogen or methyl; PA1 R.sup.4 is hydrogen; or substituted or unsubstituted C.sub.1-4 alkyl in which the substituent is selected from the group consisting of hydroxy, amino, methylthio, carboxyl, carboxamide, guanidino, phenyl and hydroxyphenyl; PA1 R.sup.5 and R.sup.6 each are independently hydrogen, C.sub.1-4 alkyl; or R.sup.5 and R.sup.6, taken together with the nitrogen atom to which they are attached, is a heterocyclic ring selected from piperazine, N-methyl piperazine, piperidine, thiomorpholine and morpholine; and PA1 R.sup.7, R.sup.8 and R.sup.9 each are independently C.sub.1-4 alkyl; or a nontoxic pharmaceutically acceptable salt or solvate thereof.
group;
or (2) if m=2, alkylene, alkylene ether, alkylene thioether, diphenylene, or napthalene. The compounds are antioxidants for organic polymers.
EPO 0-533276-A1 published on Mar. 24, 1993, shows compounds of Formula (ii): ##STR4##
wherein one of P or Q is an ortho-substituted phenyl group and the other a substituted benzyl. The Formula (ii) compounds are miticides and insecticides.
A. E. Wilder Smith disclosed in Arzneim. Forsch. (1967) 67, No.17, pp. 768-772, the preparation and study of compounds of Formula (iii): ##STR5##
wherein X is H or Cl and n is 1 or 2. The compounds have tuberculostatic properties. Formula (iii) compounds do not encompass substitution para to the hydroxyl group.
J. L. Romine, et al. in International Patent Application WO 98/04135, published Feb. 5, 1998, describe a series of diphenyl heterocycles of the Formula (iv): ##STR6##
wherein Het is a heterocyclic moiety selected from inter alia, oxadiazolone. The compounds are useful as modulators of the large conductance calcium-activated potassium channels and the starting material for the preparation of the compounds of the present invention is described therein wherein Het is 1,3,4-oxadiazol-2(3H)-one, m=1 and n=0, R.sup.c is chloro, R.sup.d is trifluoromethyl and R.sup.a, =R.sup.b =R.sup.e is hydrogen.
None of these references teach or suggest the novel compounds of the present invention.